The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Abstract

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

Somatic variation as an incidental finding in the pediatric next-generation sequencing era

“…In brief, the PPP2R1A variant was verified as a de novo change, with both maternity and paternity confirmed via in-silico analysis of trio ES data and end-point PCR of loci with high population minor allele frequency used to compare inherited genotypes (C. R. . This variant was absent from large-scale population databases (Karczewski et al 2020), has been reported in the literature with supporting in-vitro functional studies suggesting a reduction in protein activity (Houge et al 2015;Ji et al 2019) hindering binding to the regulatory subunit B55α encoded by PPP2R2A (Lenaerts et al 2021) and is predicted to be damaging by multiple computational (in silico) functional prediction algorithms (ACMG/AMP: PS2, PM2, PM_PS3, PP3). The PPP2R1A variant was verified via orthogonal Sanger sequencing of proband and parental samples and observed only in the proband sample.…”

Refractory Epilepsy in a Toddler With PPP2R1A Gene Mutation and Congenital Hydrocephalus

“…Most recently, a broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorder in 30 individuals found language delay, hypotonia, and hypermobile joints along developmental delay ranging from mild learning to severe intellectual disabilities (ID) with or without epilepsy. Individuals without B55α subunit-binding deficit had macrocephaly, less severe ID, and no seizures while impaired B55α but increased striatin binding were found biochemically more disruptive variants with associated profound ID, epilepsy, hypoplasia of corpus callosum, and occasionally microcephaly [ 8 ].…”

Protein phosphatase 2A – structure, function and role in neurodevelopmental disorders

“…HR11 to HR15 anchors PP2A-C, while the variable regulatory B subunit binds to HR1 to HR10. Recent WGS and WES studies (Houge et al, 2015;Lenaerts et al, 2021;Wallace et al, 2019;Zhang et al, 2020) have reported a total of 16 SNVs on the PP2A-Aα isoform (Fig. 2A, red; Table S1).…”